Neoproterozoic to early Paleozoic extensional and compressional history of East Laurentian margin sequences: The Moine Supergroup, Scottish Caledonides

Neoproterozoic siliciclastic-dominated sequences are widespread along the eastern margin of Laurentia and are related to rifting associated with the breakout of Laurentia from the supercontinent Rodinia. Detrital zircons from the Moine Supergroup, NW Scotland, yield Archean to early Neoproterozoic U-Pb ages, consistent with derivation from the Grenville-Sveconorwegian orogen and environs and accumulation post–1000 Ma. U-Pb zircon ages for felsic and associated mafic intrusions confirm a widespread pulse of extension-related magmatism at around 870 Ma. Pegmatites yielding U-Pb zircon ages between 830 Ma and 745 Ma constrain a series of deformation and metamorphic pulses related to Knoydartian orogenesis of the host Moinerocks. Additional U-Pb zircon and monazite data, and 40Ar/39Ar ages for pegmatites and host gneisses indicate high-grade metamorphic events at ca. 458–446 Ma and ca. 426 Maduring the Caledonian orogenic cycle.The presence of early Neoproterozoic silici clastic sedimentation and deformation in the Moine and equivalent successions around the North Atlantic and their absence along strike in eastern North America reflect contrasting Laurentian paleogeography during the breakup of Rodinia. The North Atlantic realm occupied an external location on the margin of Laurentia, and this region acted as a locus for accumulation of detritus (Moine Supergroup and equivalents) derived from the Grenville-Sveconorwegian orogenic welt, which developed as a consequence of collisional assembly of Rodinia. Neoproterozoic orogenic activity corresponds with theinferred development of convergent platemargin activity along the periphery of the supercontinent. In contrast in eastern North America, which lay within the internal parts of Rodinia, sedimentation did not commence until the mid-Neoproterozoic (ca. 760 Ma) during initial stages of supercontinent fragmentation. In the North Atlantic region, this time frame corresponds to a second pulse of extension represented by units such as the Dalradian Supergroup, which unconformably overlies the predeformed Moine succession

Emergency Bipap Ventilator For Breathing Assistance

Journal ArticleThe paper proposes the concept of a simplified ventilation device that meets the requirements for the South African Health Products Regulatory Authority (SAHPRA) approval and may be manufactured in large numbers at moderate cost to meet the requirements of the current or future pneumonic type pandemics. The paper further describes the development of such a device and presents descriptions of the final prototype. The philosophy behind the design was to take an engineering view of the problem of safe ventilation, which also meets World Health Organisation (WHO) guideline ‘Technical specifications for invasive and non-invasive ventilators for COVID-19’ (2020), whilst using the human biological responses to control the aspiration boundaries, thereby avoiding the very complex processes which simulate the breathing mechanism. The methodology employed was a conceptual design phase followed by an engineering design phase, prototyping, testing, and further developments. The concept was based on guidelines from WHO, 2020: Technical specifications for invasive and non-invasive ventilators for COVID-19: Interim guidance: paragraphs 2.1.2 and 2.2.2.(2020) and measured against the UK standard of the Medicines and Healthcare Products Regulatory Agency (MHPRA) ‘Rapidly manufactured ventilator system’ (2020). Each component of the conceptual design was developed in this way and a final prototype was assembled for independent evaluation and eventual SAHPRA evaluation. The finished prototype meets WHO guidelines for a Bi-level Positive Airway Pressure (BiPAP) system and also meets the guideline requirements for portability. The prototype also meets the initial intent regarding simplicity, functionality and cost. The further developments to mass production will reduce the part count and assembly processes, with some components to be reconfigured as disposable items, not for sterilisation or re-use. The project has shown that specialised equipment may be viewed pragmatically according to the requirement — to treat all breathing difficulties with a full specification ventilator is not possible or necessary; to assist the majority of ostensibly minor cases with a Bi-PAP system is both practical and more affordable. The intent is not to compete with the high technology commercially sourced equipment, or even the rapidly prototyped re-purposed industrial efforts worldwide, but rather to initiate some progress in the Republic of South Africa to quickly produce an abundance of these machines, to cope with the possible deficit of medical ventilators expected in future. The solution lies in a simple but failsafe device that provides assisted breathing with the option of oxygen enrichment. It is intended to be locally manufactured with the minimum of skills and is easily maintained and sterilised

Education protects against coronary heart disease and stroke independently of cognitive function: evidence from Mendelian randomization.

BACKGROUND: There is evidence that education protects against cardiovascular disease. However, it is not known whether such an effect is independent of cognition. METHODS: We performed two-sample Mendelian randomization (MR) analyses to investigate the effect of education and cognition, respectively, on risk of CHD and ischaemic stroke. Additionally, we used multivariable MR to adjust for the effects of cognition and education in the respective analyses to measure the effects of these traits independently of each other. RESULTS: In unadjusted MR, there was evidence that education is causally associated with both CHD and stroke risk [CHD: odds ratio (OR) 0.65 per 1-standard deviation (SD; 3.6 years) increase in education; 95% confidence interval (CI) 0.61-0.70, stroke: OR 0.77; 95% CI 0.69-0.86]. This effect persisted after adjusting for cognition in multivariable MR (CHD: OR 0.76; 95% CI 0.65-0.89, stroke OR 0.74; 95% CI 0.59-0.92). Cognition had an apparent effect on CHD risk in unadjusted MR (OR per 1-SD increase 0.80; 95% CI 0.74-0.85), however after adjusting for education this was no longer observed (OR 1.03; 95% CI 0.86-1.25). Cognition did not have any notable effect on the risk of developing ischaemic stroke, with (OR 0.97; 95% CI 0.87-1.08) or without adjustment for education (OR 1.04; 95% CI 0.79-1.36). CONCLUSIONS: This study provides evidence to support that education protects against CHD and ischaemic stroke risk independently of cognition, but does not provide evidence to support that cognition protects against CHD and stroke risk independently of education. These findings could have implications for education and health policy

Sinus lifting before Le Fort I maxillary osteotomy: a suitable method for oral rehabilitation of edentulous patients with skelettal class-III conditions: review of the literature and report of a case

BACKGROUND: Functional rehabilitation of patients afflicted with severe mandibular and maxillary alveolar atrophy might be challenging especially in malformed patients. METHODS: Treatment planning using sinus lifting and implant placement before Le Fort I maxillary osteotomy in a patient with severe mandibular and posterior maxillary alveolar atrophy and skelettal class-III conditions due to cleft palate are described. RESULTS: A full functional and esthetic rehabilitation of the patient was achieved by a stepwise surgical approach performed through sinus lifting as the primary approach followed by implant placement and subsequent Le Fort I maxillary osteotomy to correct the maxillo-mandibular relation. CONCLUSION: Stabilisation of the maxillary complex by a sinus lifting procedure in combination with computer aided implant placement as preorthodontic planning procedure before Le Fort I maxillary osteotomy seems to be suitable in order to allow ideal oral rehabilitation especially in malformed patients

MicroRNA Controlled Adenovirus Mediates Anti-Cancer Efficacy without Affecting Endogenous MicroRNA Activity

MicroRNAs are small non-coding RNA molecules that regulate mRNA translation and stability by binding to complementary sequences usually within the 3′ un-translated region (UTR). We have previously shown that the hepatic toxicity caused by wild-type Adenovirus 5 (Ad5WT) in mice can be prevented by incorporating 4 binding sites for the liver-specific microRNA, mir122, into the 3′ UTR of E1A mRNA. This virus, termed Ad5mir122, is a promising virotherapy candidate and causes no obvious liver pathology. Herein we show that Ad5mir122 maintains wild-type lytic activity in cancer cells not expressing mir122 and assess any effects of possible mir122 depletion in host cells. Repeat administration of 2×1010 viral particles of Admir122 to HepG2 tumour bearing mice showed significant anti-cancer efficacy. RT-QPCR showed that E1A mRNA was down-regulated 29-fold in liver when compared to Ad5WT. Western blot for E1A confirmed that all protein variants were knocked down. RT-QPCR for mature mir122 in infected livers showed that quantity of mir122 remained unaffected. Genome wide mRNA microarray profiling of infected livers showed that although the transcript level of >3900 different mRNAs changed more than 2-fold following Ad5WT infection, less than 600 were changed by Ad5mir122. These were then filtered to select mRNAs that were only altered by Ad5mir122 and the remaining 21 mRNAs were compared to predicted mir122 targets. No mir122 target mRNAs were affected by Ad5 mir122. These results demonstrate that the exploitation of microRNA regulation to control virus replication does not necessarily affect the level of the microRNA or the endogenous mRNA targets

Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 39 UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5610 10 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral disease

Spatial and temporal control of Archean tectonomagmatic regimes

Secular trends in plutonic whole-rock geochemistry pose critical, although non-unique, constraints to early Earth tectonics. Here, we present a large whole-rock geochemical (879 collated samples) dataset for granitoids from the Pilbara Craton, Western Australia, applying it to test the link between secular trends and proposed tectonic mechanisms. We show that the spatio-temporal distribution of granitoid trace element geochemistry is constrained within discrete lithotectonic blocks supporting the reconstruction of its tectonomagmatic evolution. Time-sliced geochemical contour mapping of key petrogenetic ratios indicates the craton underwent rifting ∼3.2 Ga (billion years ago), marking a transition from predominantly sodic magmatism to a broader magmatic compositional spectrum. Our results demonstrate that rift-assisted breakup of proto-cratons is a viable craton growth mechanism. We identify a possible evolutionary sequence beginning with drips and upwellings below a Paleoarchean mafic plateau, which is subsequently dismembered by rifting. These plateau fragments form rigid blocks in the Mesoarchean, between which weaker, thinner crust accommodates minor convergence and divergence manifested as short-lived mobile lid-like features before stabilization. We conclude that these features do not require an active lid, plate tectonic regime

The stability of cratons is controlled by lithospheric thickness, as evidenced by Rb-Sr overprint ages in granitoids

The ancient cores of modern continents, cratons, are the oldest blocks of “stable” lithosphere on Earth. Their long-term survival relies on the resistance of their underlying thick, strong, and buoyant mantle keels to subsequent recycling. However, the effect of substantial geographical variations in keel thickness on the post-assembly behaviour and mass movement within these continental cores remains unknown. Here, we demonstrate that the spatial distribution of fluid-reset in-situ Rb-Sr ages for Paleo-Mesoarchean (3.6–2.8 billion years ago; Ga) granitoids of the Pilbara Craton, Australia shows remarkable correlation with independently-constrained lithospheric thickness models. Without craton-wide heating/magmatic events, these anomalously young Rb-Sr ages document episodes of fluid infiltration into granitoid complexes as a response to lithospheric reactivation by far-field stresses. This correlation implies that craton-wide fluid mobilization triggered by extra-cratonic Neoarchean to Mesoproterozoic (2.8–1.0 Ga) tectonic events is facilitated by variations in lithospheric strength and thickness. Compared to areas of older overprints, the two-thirds of the craton comprised of younger reset ages is underlain by comparatively thin lithosphere with higher susceptibility to reactivation-assisted fluid flow. We propose that even the strongest, most pristine cratons are less stable and impermeable than previously thought, as demonstrated by the role of granitoid complexes and cratons as selective lithospheric “sponges” in response to minor tectonic forces. Therefore, variations in lithospheric thickness, likely attained before cratonization, exert a crucial control on billions of years of fluid movement, elemental redistribution and mineralization within ancient continental nuclei